SNAREopathies: Mechanisms of neuropsychiatric genetic diseases of the SNARE complex: towards therapeutic intervention

Incorrect signal transmission between neurons often occurs in association with major brain diseases, and can lead to epileptic seizures at any stage in life. Proteins from the SNARE complex play an important role in signal transmission. They regulate the release of signalling molecules from one neuron to the next. Patients with mutations in these proteins suffer from a wide range of seizure types and other neuropsychiatric symptoms, and many of them respond poorly to available medications. By introducing the exact same mutated proteins found in patients into the brain cells of developing zebrafish, we can see how these proteins change the structure and functioning of the brain. Different chemical compounds are given to these fish, to see if they can normalize brain function and identify new potential drugs. Any findings will be confirmed in mouse and cell models in collaboration with international partners.

The development of zebrafish models for SNAREopathies is a valuable contribution to the field. The limited number of previous animal models available are rodent based, which makes drug testing in an in vivo setting extremely costly and time consuming. The models developed in this project will be used to prescreen larger sets of compounds, hits of which can then be further validated in rodents. Already, based on personal communications about our models, there has been national and international interest to test drug candidates with potential anti-epileptic and disease modifying activity of co-morbid features in the models generated in this study. Several models generated in the zebrafish also mimic patient mutations corresponding to severe, refractory, early onset neurodevelopmental syndromes. To our knowledge, these are the first animal models to be generated for such mutations. Use of these models for drug discovery will be of added value towards a precision medicine based approach.

Epileptic seizures are important symptoms of several major brain disorders. Ample evidence suggests that synaptic dysfunction is a central aspect of these diseases leading to disturbed excitation/inhibition balance and dysfunction of neuronal networks. Despite some mechanistic insight, treatment success is often limited, as one third of epilepsy patients do not respond to available drugs. To find more tailor-made solutions for cases in which generic epilepsy treatment is ineffective, we will gain mechanistic insight in the diverse routes that lead from synaptic dysfunction to seizure phenotypes and search for effective therapies. This proposal unites world-leading experts in the genetics of epilepsy, synapse biology, structural biology, and in vivo behavioral screens to characterize the molecular, synaptic and network dysfunctions of epilepsy-causing mutations in key proteins of the synaptic vesicle release machinery, two central components of the SNARE-complex and one co-factor. Mutations in the respective genes lead to a wide spectrum of seizure phenotypes, many of which respond poorly to available antiepileptic drugs. We will characterize the mechanisms of the different mutations in a concerted approach using a variety of rodent and human model systems and provide screening platforms in human neurons and zebrafish to identify novel therapeutic compounds. Together, these studies will provide a unique insight into the diverse routes from synapse dysfunction to seizure phenotypes and provide important handles for better patient stratification and personalized treatments.